Searching for the genetic factors predisposing to PBC

• Project/Area Number: 15K06908
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical genome science
• Research Institution: The University of Tokyo
• Principal Investigator: KAWASHIMA Minae 東京大学, 大学院医学系研究科(医学部), 客員研究員 (00396706)
• Co-Investigator(Renkei-kenkyūsha): NAKAMURA Minoru 長崎医療センター, 臨床研究センター, 客員研究員 (40217906) ; TOKUNAGA Katsushi 東京大学, 大学院医学系研究科, 教授 (40163977) ; NISHIDA Nao 国立国際医療研究センター, 肝炎・免疫研究センター, 上級研究員 (50456109)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: PBC / 遺伝要因探索 / ゲノムワイド関連解析 / replication study / 層別化解析 / 国際共同研究 / 原発性胆汁性胆管炎（PBC） / ゲノムワイド関連解析（GWAS） / 層別化解析（悪性化） / ヒト白血球抗原（HLA） / Imputtaion / 機能解析 / 原発性胆汁性肝硬変 / Replication Study

Outline of Final Research Achievements

Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease, presumably caused by autoimmune reactions against biliary epithelial cells, leading to liver cirrhosis and hepatic failure. The incidence and prevalence of PBC range from 0.33 to 5.8 and from 2 to 40 per 100,000 inhabitants, respectively, in different geographical areas. Additionally, it is much more common in women, with a sex ratio of at least 7:1 female to male. The high concordance rate in monozygotic twins compared to dizygotic twins and familial clustering of PBC patients indicates the involvement of strong genetic factors in the development of PBC. For the identification of susceptibility genetic factors for pathology, progression, and pathology of PBC, a genome-wide association study (GWAS) and classification analyses were performed in a large number of Japanese individuals (1381 PBC cases and 1505 healthy controls). Functional analyses in vivo and in silico were also performed.

Research Products

• [Int'l Joint Research] アルバータ大学(米国)
• [Int'l Joint Research] ケンブリッジ大学/オックスフォード大学(英国)
• [Int'l Joint Research] 上海大学(中国)
• [Int'l Joint Research] Humanitas大学(イタリア)
• [Int'l Joint Research] ケンブリッジ大学(英国)
• [Int'l Joint Research] 上海大学(中国)
• [Int'l Joint Research] Humanitas大学(イタリア)
• [Int'l Joint Research] Humanitas University(イタリア)
• [Int'l Joint Research] Cambridge University(英国)
• [Journal Article] Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis (2017)
  • Author(s): Hitomi Yuki、Kojima Kaname、Kawashima Minae、Kawai Yosuke、Nishida Nao、Aiba Yoshihiro、Yasunami Michio、Nagasaki Masao、Nakamura Minoru、Tokunaga Katsushi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 2904-2904
  • DOI: 10.1038/s41598-017-03067-3
  • Peer Reviewed / Open Access
• [Journal Article] Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary cholangitis in a Japanese population (2017)
  • Author(s): Yasunami Michio、Nakamura Hitomi、Tokunaga Katsushi、Kawashima Minae、Nishida Nao、Hitomi Yuki、Nakamura Minoru
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 11093-11093
  • DOI: 10.1038/s41598-017-11148-6
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population (2017)
  • Author(s): Kawashima M, Honda M, Nakamura M. et al.
  • Journal Title: Hum Mol Genet. Volume: 26 Issue: 3 Pages: 650
  • DOI: 10.1093/hmg/ddw406
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy. (2016)
  • Author(s): Sun Y, Irwanto A, Toyo-Oka L, Hong M, Liu H, Andiappan AK, Choi H, Hitomi Y, Yu G, Yu Y, Bao F, Wang C, Fu X, Yue Z, Wang H, Zhang H, Kawashima M, Kojima K, Nagasaki M, Nakamura M, Yang SK, Ye BD, Denise Y, Rotzschke O, Song K, Tokunaga K, Zhang F, Liu J.
  • Journal Title: Sci Rep. Volume: 10(6) Issue: 1 Pages: 31429-31429
  • DOI: 10.1038/srep31429
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human primary biliary cirrhosis-susceptible allele of rs4979462 enhances TNFSF15 expression by binding NF-1. (2015)
  • Author(s): Hitomi Y, Kawashima M, Aiba Y, Nishida N, Matsuhashi M, Okazaki H, Nakamura M, Tokunaga K
  • Journal Title: Human Genetics Volume: 印刷中 Issue: 7 Pages: 737-747
  • DOI: 10.1007/s00439-015-1556-3
  • Peer Reviewed
• [Journal Article] Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population (2015)
  • Author(s): Yoshihiro Aiba, Keiko Yamazaki, Nao Nishida, Minae Kawashima, Yuki Hitomi, Hitomi Nakamura, Atsumasa Komori, Yuta Fuyuno, Atsushi Takahashi, Takaaki Kawaguchi, Masakazu Takazoe, Yasuo Suzuki, Satoshi Motoya Toshiyuki Matsui Motohiro Esaki, Takayuki Matsumoto, Michiaki Kubo, Katsushi Tokunaga, Minoru Nakamura
  • Journal Title: Journal of Human Genetics Volume: 印刷中 Issue: 9 Pages: 525-531
  • DOI: 10.1038/jhg.2015.59
  • NAID: 40020589506
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Imputation analysis using reference panel of 1,070 Japanese individuals (1KJPN) and in silico / in vitro functional analyses identified functional variants for primary biliary cirrhosis (PBC) susceptibility. (2017)
  • Author(s): Hitomi Y, Kojima K, Kawashima M, Kawai Y, Nishida N, Aiba Y, Yasunami M, Nagasaki M, Nakamura M, Tokunaga K
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2017-04-03
  • Int'l Joint Research
• [Presentation] 原発性胆汁性胆管炎（PBC）感受性遺伝子NFKB1/MANBAを対象とした、第一義的な機能的遺伝子 多型の同定研究 (2017)
  • Author(s): 人見 祐基、仲谷 健、小島 要、 西田 奈央、河合 洋介、川嶋 実苗、 相葉 佳洋、長崎 正朗、中村 稔、 徳永 勝士
  • Organizer: 日本人類遺伝学会
• [Presentation] 疾患リスクアレル頻度分布の非対称性に関する統計数理解析 (2017)
  • Author(s): 城戸 隆、川嶋 実苗、菊地 進一、 鎌谷 直之
  • Organizer: 日本人類遺伝学会
• [Presentation] ゲノムワイド関連解析により同定された産科抗リン脂質抗体症候群の新たな発症関連遺伝子 (2017)
  • Author(s): 大前 陽輔、杉浦 真弓、川嶋 実苗、 豊岡 理人、Seik-Soon Khor、澤井 裕美、堀田 哲也、 渥美 達也、村島 温子、藤田 太輔、 藤田 富雄、森本 真司、森下 英理子、 北折 珠央、片野 衣江、尾崎 康彦、 徳永 勝士
  • Organizer: 日本人類遺伝学会
• [Presentation] 研究データの共有におけるゲノムデータや臨床情報の取り扱いについて (2017)
  • Author(s): 川嶋実苗
  • Organizer: 日本人類遺伝学会
  • Invited
• [Presentation] NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population. (2017)
  • Author(s): M. Kawashima, N. Nishida, Y. Hitomi, K. Kojima, Y. Kawai, Y. Aiba, H. Nakamura, M. Nagasaki, K. Tokunaga, M. Nakamura
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Identification of the primary functional variants in primary biliary cholangitis susceptibility gene loci NFKB1/MANBA. (2017)
  • Author(s): Y. Hitomi, K. Nakatani, K. Kojima, N. Nishida, Y. Kawai, M. Kawashima, Y. Aiba, M. Nagasaki, M. Nakamura, K. Tokunaga
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Controlled-access databases for genetic and phenotypic human data in Japan. (2017)
  • Author(s): Y. Kodama, A. Fukuda, J. Mashima, M. Minowa, M. Kawashima, K. Miyazaki, N. Mitsuhashi, E. Kaminuma, O. Ogasawara, K. Okubo, Y. Nakamura, T. Takagi
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] GWAS polygenic model approach applied to primary biliary cholangitis (PBC) in a Japanese population. (2017)
  • Author(s): O. Gervais, K. Ueno, K. Kojima, Y. Aiba, M. Kawashima, Y. Kawai, Y. Hitomi, K. Tokunaga, M. Nakamura, M. Nagasaki
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Genome-wide association study identifies PRKCB as a novel genetic factor for primary biliary cirrhosis in the Japanese population (2016)
  • Author(s): M. Kawashima , Y. Hitomi , N. Nishida , K. Kojima , Y. Kawai , H. Nakamura , K. Chayama , Y. Aiba , M. Nagasaki , K. Tokunaga , M. Nakamura , PBC Consortium in Japan (PBCCSJ)
  • Organizer: American Society of Human Genetics 2017 Annual Meeting
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-10-18
  • Int'l Joint Research
• [Presentation] Identification of the primary functional variants for Primary biliary cirrhosis (PBC) susceptibility loci by high-density association mapping and in silico / in vitro functional analyses. (2016)
  • Author(s): Hitomi Y, Kojima K, Kawashima M, Kawai Y, Nishida N, Aiba Y, Yasunami M, Nagasaki M, Nakamura M, Tokunaga K
  • Organizer: American Society of Human Genetics 2017 Annual Meeting
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-10-18
• [Presentation] ゲノムワイド関連解析から同定された日本人原発性胆汁性肝硬変症発症に抑制的な HLA ハプロ タイプの効果 (2015)
  • Author(s): 安波 道郎、中村 仁美、徳永 勝士、川嶋 実苗、西田 奈央、人見 祐基、中村 稔
  • Organizer: 第 60 回日本人類遺伝学会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-10-16
• [Presentation] Dissection of HLA class II in Japanese primary biliary cirrhosis: epistasis of protective HLA-DQ allele and additional contribution of HLA-DP allele. (2015)
  • Author(s): M. Yasunami; H. Nakamura; K. Tokunaga; M. Kawashima; N. Nishida; Y. Hitomi; M. Nakamura
  • Organizer: American Society of Human Genetics 2015
  • Place of Presentation: Baltimore (U.S.A.)
  • Year and Date: 2015-10-07
  • Int'l Joint Research
• [Book] 実験医学 (2017)
  • Author(s): 川嶋実苗
  • Publisher: 羊土社
  • ISBN: 9784758103664
• [Remarks] 東京大学大学院医学系研究科人類遺伝学教室HP
  • URL: http://www.humgenet.m.u-tokyo.ac.jp/
• [Remarks] 東京大学大学院医学系研究科人類遺伝学教室HP
  • URL: http://www.humgenet.m.u-tokyo.ac.jp/research/1-2.html